Multimeric ACE2-IgM fusions as broadly active antivirals that potently neutralize SARS-CoV-2 variants

Fusion of ACE2 to IgM-Fc results in hexameric ACE2-IgM-Fc proteins with potent virus neutralization efficiency of patient-isolated SARS-CoV and SARS-CoV-2 variants. Coronavirus infections are a world-wide threat to human health. A promising strategy to develop a broadly active antiviral is the use of fusion proteins consisting of an antibody IgG Fc region and a human ACE2 domain to which the viral spike proteins bind. Here we create antiviral fusion proteins based on IgM scaffolds. The hexameric ACE2-IgM-Fc fusions can be efficiently produced in mammalian cells and they neutralize the infectious virus with picomolar affinity thus surpassing monomeric ACE2-IgM-Fc by up to 96-fold in potency. In addition, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 omicron variant in comparison to prototypic SARS-CoV-2. Taken together, these multimeric IgM fusions proteins are a powerful weapon to fight coronavirus infections.

Automated summary

Fusion of ACE2 with IgM-Fc produces hexameric ACE2-IgM-Fc proteins that neutralize patient-isolated SARS-CoV and SARS-CoV-2 variants effectively. These fusion proteins can be produced efficiently in mammalian cells and exhibit up to 96-fold higher potency in neutralizing the infectious virus compared to monomeric ACE2-IgM-Fc. Furthermore, the ACE2-IgM fusion shows increased neutralization efficiency for the highly infectious SARS-CoV-2 Omicron variant compared to the prototype SARS-CoV-2.